TRPA1 is a non-selective cation channel related to pain sensation in humans. TRPA1 is found in sensory neurons and functions as a signal transduction receptor linking inflammation to pain. Activation of TRPA1 can cause pain by inducing firing of nociceptive neurons and driving central sensitization in the spinal cord. TRPA1 stimulation can also increase firing of sensory neurons, leading to the release of pro-inflammatory neuropeptides such as NK-A, substance P and CGRP (which induce vasodilation and help recruit immune cells). A variety of endogenous reactive compounds produced during inflammation activate TRPA1 (including 4-hydroxynonenal released during liposome peroxidation; cyclopentane prostaglandins synthesized by COX enzymes; hydrogen peroxide produced by oxidative stress). TRPA1 can also be activated by a variety of stimuli, including natural products (e.g., allyl isothiocyanate, or AITC), environmental irritants (e.g., acrolein), amphipathic molecules (e.g., trinitrophenol and chlorpromazine) and pharmacological agents. Activation of TRPA1 also sensitizes TRPA1 to cold. Furthermore, a gain-of-function mutation in TRPA1 causes familial episodic pain syndrome; patients suffering from this condition have episodic pain that may be triggered by cold. (Kremeyer et al., Neuron. 2010 Jun. 10; 66(5):671-80). Thus, TRPA1 is believed to play a role in pain, including pain related to nerve damage, cold allodynia and inflammatory pain.
TRPA1 inhibitor compounds can be used to treat pain. Compounds that inhibit the TRPA1 ion channel can be useful, for example, in treating conditions ameliorated, eliminated or prevented by inhibition of the TRPA1 ion channel (e.g., medical conditions causing pain). Inhibition of TRPA1 (e.g., by genetic ablation and chemical antagonism) has been shown to result in reduced pain behavior in mice and rats. Knockout mice lacking functional TRPA1 have diminished nociceptive responses to TRPA1 activators (including AITC, formalin, acrolein, 4-hydroxynonenal) and, in addition, have greatly reduced thermal and mechanical hypersensitivity in response to the inflammatory mediator bradykinin (e.g., Kwan, K. Y. et al. Neuron 2006, 50, 277-289; Bautista, D. M. et al. Cell 2006, 124, 1269-1282). In animal pain models, down regulation of TRPA1 expression by gene specific antisense oligonucleotides prevented and reversed cold hyperalgesia induced by inflammation and nerve injury (See, e.g., Obata, K. et al., Journal of Clinical Investigation 2005, 115, 2393-2401; Jordt, S. E. et al., Nature 2004, 427, 260-265; Katsura, H. et al., Exploratory Neurology 2006, 200, 112-123). TRPA1 inhibitor compounds are also effective in a variety of rodent pain models. TRPA1 inhibitors have been shown to reduce mechanical hypersensitivity and cold allodynia following inflammation induced by Complete Freund's Adjuvant (without altering normal cold sensation in naïve animals) and also to improve function in the rat mono-iodoacetate osteoarthritis model. (See, del Camino, D. et al. (2010). TRPA1 contributes to cold hypersensitivity. J Neurosci 30, 15165-15174; and Chen, J. et al., (2011). Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain 152, 1165-72.) TRPA1 inhibitor compounds have demonstrated reduced pain behavior in rodents injected with AITC (mustard oil), formalin, cinnamaldehyde, acrolein and other TRPA1 activators. (See, Jordt, S. E. et al., Nature 2004, 427, 260-265; Chen, J. et al., (2011). Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain 152, 1165-72.)
Recently, a TRPA1 inhibiting compound was disclosed as compound 1 in PCT patent application PCT/US2009/069146 (published as WO2010/075353A1 on Jul. 1, 2010):

However, there remains a need to identify compounds that safely modulate (e.g., inhibit) ion channels involved in pain, including a need for pharmaceutical compositions that inhibit the TRPA1 ion channel. In particular, there is a need to identify compounds that inhibit TRPA1 without serum biomarkers of hepatotoxicity. Such compounds are useful, for example, both as research tools and as therapeutic agents (e.g., for the treatment of pain).